Mechanism of action of vasopressin as a calcium mobilizing hormone.

Mechanisms of lithium‐vasopressin interaction in rabbit cortical collecting tubule.

pathway in vasopressin and oxytocin ..

cAMP, once formed, serves to modulate inotropy, chronotropy and lusitropy by inducing PKA phosphorylation of contractile proteins, ion channels, enzymes of intermediary metabolism and other regulatory proteins. Though cAMP is the major activator of PKA, PKA can also be formed independent of cAMP. Vasoactive peptides Endothelin-1 and AngiotensinII activate PKA by inducing phosphorylation and degradation of the inhibitor of IKappaB, subsequently releasing PKAc from inhibition by IKappaB. GN-Alpha13, upon interaction with protein kinase AKAP110 (A-Anchoring Protein-110), induces release of the PKAc from the AKAP110-PKAr complex, resulting in the PKA activation. GN-Alpha13 activates MEKK1 (MAPK/ERK Kinase Kinase-1) and RhoA via two independent pathways, which induce phosphorylation and degradation of IKappaB-Alpha, presumably through activation of IKK (IKappaB Kinase), leading to release and activation of PKA catalytic subunit. PKAc can be regulated by mechanisms that are cAMP independent. The phosphorylation of the p65/RelA subunit of transcription factor NF-KappaB that is catalyzed by PKAc is independent of cAMP. NF-KappaB is maintained in an inactive state in the cytosol by association with the inhibitor protein IKappaB. The catalytic subunit of PKA is also inactivated by binding to IKappaB, forming an NF-KappaB–IKappaB–PKAc complex. Upon lipopolysaccharide stimulation, IKappaB Kinase phosphorylates IKappaB, thereby targeting it for proteasomal degradation. PKAc is released in an active form and phosphorylates p65/RelA subunit of NF-KappaB on Ser-276, resulting in increased transactivating activity of NF-KappaB independent of nuclear translocation and increased DNA binding. Rather, increased transactivation is due to enhanced binding to the transcriptional coactivators, CBP/p300. PKAc also lead to VASP (Vasodilator-Stimulated Phosphoprotein) phosphorylation. PKA also activates NFAT5, independent of cAMP. PKAc stimulation of NFAT5 transactivating activity could be similar to that found for NF-KappaB (Ref.6 & 7).

Effects of calcium on ADH action in the cortical collecting tubule perfused in vitro.

Molecular Mechanisms of Vasopressin Action in the …

Activated PKA phosphorylates endothelial MLCK (Myosin Light Polypeptide Kinase), thereby reducing its activity, leading to decreased basal MLC (Myosin Light Chain) phosphorylation. Elevation of intracellular cAMP levels and activation of PKA stimulate phosphorylation of the Actin-binding proteins Filamin and Adducin and focal adhesion proteins Paxillin and FAK (Focal Adhesion Kinase), as well as the disappearance of stress fibers and F-actin (Filamentous Actin) accumulation in the membrane ruffles. PKA-mediated modulation of Rho GTPase activity is another potentially important mechanism for regulation of Actin cytoskeletal organization. Elevation of intracellular cAMP and increased PKA activity attenuates RhoA activation via RhoA phosphorylation at Ser188, which decreases Rho association with Rho-Kinase. Rho Kinase regulates Myosin-II and cell contraction by catalyzing phosphorylation of the regulatory subunit of Myosin phosphatase, PPtase1 (Protein Phosphatase-1), by inhibiting its catalytic activity, which results in an indirect increase in RLC (Regulatory Light Chain of Myosin) phosphorylation. Inactivation of Rho Kinase also directly increases RLC phosphorylation. PKA activation also increases interaction of RhoA with Rho-GDI (Rho-GDP Dissociation Inhibitor) and translocation of RhoA from the membrane to the cytosol. Thus the overall effect of PKA on RhoA is the inhibition of RhoA activity and stabilization of cortical Actin cytoskeleton. PKA also controls phosphatase activity by phosphorylation of specific PPtase1 inhibitors, such as DARPP32 (Dopamine-and cAMP-Regulated Phosphoprotein). Neurotransmitters enhance DARPP32 interaction via GPCRs, which leads to suppression of PPtase1 activity, when DARPP32 is phosphorylated at Thr-34 (Threonine-34) position. PPtase1 checks the phosphorylation of CREB (cAMP Responsive element binding Protein), CREM (cAMP Response Element Modulator) and ATF1 (Activating Transcription Factor-1) so that they are able to interact with the co-activators like CBP (CREB-Binding Protein) and p300. PKA also activates CREB and controls the expression of critical genes such as BDNF (Brain-Derived Neurotrophic Factor). Similarly, phosphorylation of NF-KappaB (Nuclear Factor-KappaB) by PKA is necessary for transcriptional activation and interaction with CBP (Ref.10 & 11).

Vasopressin‐induced changes in the three‐dimensional structure of toad bladder apical surface.

These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.